A Dimerization Site at SCR-17/18 in Factor H Clarifies a New Mechanism for Complement Regulatory Control

Complement Factor H (CFH), with 20 short complement regulator (SCR) domains, regulates the alternative pathway of in part through interaction its C-terminal SCR-19 and SCR-20 domains host cell-bound C3b anionic oligosaccharides. In solution, CFH forms small amounts oligomers, one self-association sites being SCR-16/20 domains. order to correlate function dimer formation occurrence rare disease-associated variants SCR-16/20, we identified dimerization site SCR-16/20. For this, expressed, Pichia pastoris , five six fragments this one-three (SCR-19/20, SCR-18/20, SCR-17/18, SCR-16/18, SCR-17 SCR-18). Size-exclusion chromatography suggested that SCR occurred several fragments. Dimer was clarified using analytical ultracentrifugation, where quantitative c(s) size distribution analyses showed SCR-19/20 monomeric, SCR-18/20 slightly dimeric, SCR-16/18 SCR-18 more formation, SCR-17/18 were primarily dimeric dissociation constants ~5 µM. The combination these results located at SCR-18. X-ray solution scattering experiments molecular modelling fits confirmed be a side-by-side association two We propose enables higher concentrations achieved when are bound cell surfaces protect better during inflammation. genetic throughout renal disease.